The occurrence of brain metastases among breast cancer patients is currently rising with approximately 20-25% incidence rates, underlining the importance of the identification of new therapeutic and ...prognostic markers. We have previously screened for new markers for brain metastasis by array CGH. We found that loss of 11p15 is common among these patients. In this study, we investigated the clinical significance of loss of 11p15 in primary breast cancer (BC) and breast cancer brain metastases (BCBM). 11p15 aberration patterns were assessed by allelic imbalance (AI) analysis in primary BC (n = 78), BCBM (n = 21) and metastases from other distant sites (n = 6) using six different markers. AI at 11p15 was significantly associated with BCBM (p = 0.002). Interestingly, a subgroup of primary BC with a later relapse to the brain had almost equally high AI rates as the BCBM cases. In primary BC, AI was statistically significantly associated with high grade, negative hormone receptor status, and triple-negative (TNBC) tumors. Gene expression profiling identified PRKCDBP in the 11p15 region to be significantly downregulated in both BCBM and primary BC with brain relapse compared to primary tumors without relapse or bone metastasis (fdr<0.05). qRT-PCR confirmed these results and methylation was shown to be a common way to silence this gene. In conclusion, we found loss at 11p15 to be a marker for TNBC primary tumors and BCBM and PRKCDBP to be a potential target gene in this locus.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Breast cancer brain metastases (BCBM) are detected with increasing incidence. In order to detect potential genes involved in BCBM, we first screened for genes down-regulated by methylation in cell ...lines with site-specific metastatic ability. The expression of five genes, CADM1, SPARC, RECK, TNFAIP3 and CXCL14, which were also found down-regulated in gene expression profiling analyses of BCBM tissue samples, was verified by qRT-PCR in a larger patient cohort. CADM1 was chosen for further down-stream analyses. A higher incidence of CADM1 methylation, correlating with lower expression levels, was found in BCBM as compared to primary BC. Loss of CADM1 protein expression was detected most commonly among BCBM samples as well as among primary tumors with subsequent brain relapse. The prognostic role of CADM1 expression was finally verified in four large independent breast cancer cohorts (n=2136). Loss of CADM1 protein expression was associated with disease stage, lymph node status, and tumor size in primary BC. Furthermore, all analyses revealed a significant association between loss of CADM1 and shorter survival. In multivariate analyses, survival was significantly shorter among patients with CADM1-negative tumors. Loss of CADM1 expression is an independent prognostic factor especially associated with the development of brain metastases in breast cancer patients.
Abstract
Metastatic breast cancer remains essentially incurable, with mortality being especially high in patients who develop brain metastases. Approximately 15% of all epithelial tumors metastasize ...to the brain, with incidence rates highly dependent on the primary tumor type. Apparently, the brain microenvironment is specifically permissive for the out-growth of tumor cells from some carcinomas but not others.
In a previous study we screened by array CGH primary breast tumors and brain metastases. A 10MBp loss at 11pter-p15.4 was found in 70 % of the brain metastases whereas only 15% of the early stage primary tumors showed loss of 11p. In this study the aberration pattern of 11p was verified by microsatellite analysis in primary breast tumors and brain metastases. Six markers with an average spacing of 2 MBp were analyzed at 11p15.5-p15.4. Allelic imbalance (AI) at 11p was found in 26% (11/42) of the primary tumors whereas 71.4% (15/21) of brain metastases showed AI (p=0.001). In primary tumors the occurrence of AI was associated with high grade (p=0.03) and positive lymph node status (p=0.02). Interestingly, primary tumors with a brain relapse showed an equally high AI rate (75%) as the brain metastases (71%) in contrast to primary tumors without a relapse (26%). Furthermore, two matched pairs of primary tumors and brain metastases showed equal aberrations patterns and the third matched pair showed an enlarged AI of 11p, indicating that loss of 11p is defining a specific subgroup of breast cancer patients with a high risk of brain relapse.
In summary, these results indicate an accumulation of chromosomal imbalances during the carcinoma-metastasis sequence and the possible involvement of loss of 11p in brain metastasis formation.
Citation Format: {Authors}. {Abstract title} abstract. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4827. doi:10.1158/1538-7445.AM2011-4827
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